Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study.

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From: The Lancet(Vol. 399, Issue 10333)
Publisher: Elsevier B.V.
Document Type: Clinical report
Length: 1,499 words

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Abstract :

Summary Background Direct-acting oral anticoagulant use for stroke prevention in atrial fibrillation is limited by bleeding concerns. Asundexian, a novel, oral small molecule activated coagulation factor XIa (FXIa) inhibitor, might reduce thrombosis with minimal effect on haemostasis. We aimed to determine the optimal dose of asundexian and to compare the incidence of bleeding with that of apixaban in patients with atrial fibrillation. Methods In this randomised, double-blind, phase 2 dose-finding study, we compared asundexian 20 mg or 50 mg once daily with apixaban 5 mg twice daily in patients aged 45 years or older with atrial fibrillation, a CHA.sub.2DS.sub.2-VASc score of at least 2 if male or at least 3 if female, and increased bleeding risk. The study was conducted at 93 sites in 14 countries, including 12 European countries, Canada, and Japan. Participants were randomly assigned (1:1:1) to a treatment group using an interactive web response system, with randomisation stratified by whether patients were receiving a direct-acting oral anticoagulant before the study start. Masking was achieved using a double-dummy design, with participants receiving both the assigned treatment and a placebo that resembled the non-assigned treatment. The primary endpoint was the composite of major or clinically relevant non-major bleeding according to International Society on Thrombosis and Haemostasis criteria, assessed in all patients who took at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT04218266, and EudraCT, 2019-002365-35. Findings Between Jan 30, 2020, and June 21, 2021, 862 patients were enrolled. 755 patients were randomly assigned to treatment. Two patients (assigned to asundexian 20 mg) never took any study medication, resulting in 753 patients being included in the analysis (249 received asundexian 20 mg, 254 received asundexian 50 g, and 250 received apixaban). The mean age of participants was 73*7 years (SD 8*3), 309 (41%) were women, 216 (29%) had chronic kidney disease, and mean CHA.sub.2DS.sub.2-VASc score was 3*9 (1*3). Asundexian 20 mg resulted in 81% inhibition of FXIa activity at trough concentrations and 90% inhibition at peak concentrations; asundexian 50 mg resulted in 92% inhibition at trough concentrations and 94% inhibition at peak concentrations. Ratios of incidence proportions for the primary endpoint were 0*50 (90% CI 0*14--1*68) for asundexian 20 mg (three events), 0*16 (0*01--0*99) for asundexian 50 mg (one event), and 0*33 (0*09--0*97) for pooled asundexian (four events) versus apixaban (six events). The rate of any adverse event occurring was similar in the three treatment groups: 118 (47%) with asundexian 20 mg, 120 (47%) with asundexian 50 mg, and 122 (49%) with apixaban. Interpretation The FXIa inhibitor asundexian at doses of 20 mg and 50 mg once daily resulted in lower rates of bleeding compared with standard dosing of apixaban, with near-complete in-vivo FXIa inhibition, in patients with atrial fibrillation. Funding Bayer. Author Affiliation: (a) Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA (b) Duke University Medical Center, Durham, NC, USA (c) University of Perugia Stroke Unit, Perugia, Italy (d) Population Health Research Institute, McMaster University, Hamilton, ON, Canada (e) Hamilton Health Services, Hamilton, ON, Canada (f) Division of Medical and Radiological Sciences, University of Edinburgh, Edinburgh, UK (g) Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (h) National Heart and Lung Institute, Imperial College London, London, UK (i) University of Hertfordshire, Hatfield, UK (j) University Hospital Motol, Prague, Czech Republic (k) Bayer, Wuppertal, Germany * Correspondence to: Dr Jonathan P Piccini, Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC 27705, USA (footnote)* The PACIFIC-AF Investigators are listed in full in the Byline: Jonathan P Piccini, MD [jonathan.piccini@duke.edu] (a,b), Prof Valeria Caso, MD (c), Prof Stuart J Connolly, MD (d,e), Prof Keith A A Fox, MB ChB (f), Prof Jonas Oldgren, MD (g), W Schuyler Jones, MD (a,b), Prof Diana A Gorog, MD (h,i), Václav Durdil, MD (j), Thomas Viethen, MD (k), Christoph Neumann, PhD (k), Hardi Mundl, MD (k), Prof Manesh R Patel, MD (a,b), Johann Auer, Martin Hubauer, Sead Pandzic, Eva Preishuber, Carina Primus-Grabscheit, Dietmar Reitgruber, Florian Schmalzer, Christopher Adlbrecht, Andreas Schober, Johannes Hajos, Christoph Keil, Alexandra Schratter, Matthias Frick, Magdalena Anna Benda, Maximilian Mächler, Beatrix Mutschlechner, Christoph Saely, Lukas Sprenger, Michael Lichtenauer, Miriam Eber, Uta Hoppe, Tobias Kolbitsch, Peter Michael Jirak, Moritz Mirna, Robert Schönbauer, Jutta Bergler-Klein, Christian Hengstenberg, Stefan Stojkovic, Daniel Scherr, Martin Manninger-Wünscher, Ursula Rohrer, Markus Stühlinger, Wilfried Schgoer, Jana Schwarzl, Helmut Pürerfellner, Michael Derndorfer, Christian Ebner, Veronika Eder, Georgios Kollias, Thomas Sturmberger, Stefan Sieghartsleitner, Johan Vijgen, Peter Koopman, Karl Dujardin, Wim Anné, Michel De Ceuninck, Rene Tavernier, Mattias Duytschaever, Sébastien Knecht, Luc Missault, Yves Vandekerckhove, Tom Rossenbacker, Bavo Ector, Filip Charlier, Philippe Debruyne, Willem Dewilde, Luc Janssens, John Roosen, Bart Vankelecom, Hein Heidbuchel, Michiel Delesie, Gert Vervoort, Hans Rombouts, Thomas Vanassche, Matthias Engelen, Peter Verhamme, Rik Willems, Christian Constance, Nicolas Pranno, Jafna Cox, Iqbal Bata, Laurent Macle, Martin Aguilar, Julia Cadrin Tourigny, Marc Dubuc, Katia Dyrda, Peter Guerra, Paul Khairy, Blandine Mondésert, Léna Rivard, Denis Roy, Rafik Tadros, Mario Talajic, Bernard Thibault, Isabelle Nault, Louis Blier, Jean Champagne, Franck Molin, Gilles O'Hara, François Philippon, Benoit Plourde, Jean-François Sarrazin, Christian Steinberg, Zdenek Coufal, David Balazsik, Michal Mikulica, Jakub Zapeca, Ondrej Cermak, Tomas Drasnar, Matej Falc, Josef Hornof, Blazej Racz, Danica Weissova, Hana Linkova, Eva Paskova, Robert Petr, Andrea Sirakova, Jiri Kettner, Ales Benak, Martin Holek, Ivo Podpera, Monika Podperova, Vlastimil Vancura, Tomas Jandik, Jiri Smid, Vratislav Dedek, Jan Banik, Vaclav Durdil, Tomas Hnat, Nicolas Lellouche, Ségolène Rouffiac, Guillaume Taldir, Valentin Bridonneau, Philippe Couffon, Magalie Daudin, Cécile Hamon, Jonathan Lacaze, Anne Quentin, Christophe Thebault, Emmanuel Boiffard, Olivier Billon, Fabien Miette, Hervé Pouliquen, Guillaume Turlotte, Hervé Gorka, Franck Albert, Sandrine Bayle, Reda Bensaid, Madalina Dasoveanu, Thibaud Demichili, Teodora Dutoiu, Cliff Khalil, Caterina Loghin, Grégoire Range, Laurent Roussel, Pierre Socié, Christophe Thuaire, Fabrice Extramiana, Vincent Algalarrondo, Haten Boughanmi, Noreddine El Mansour, Usman Mohammad, Romain Sellier, Meyer Elbaz, Clémence Laperche, Philippe Maury, Robert Kiss, Tunde Borsanyi, Zoltan Gingl, Balaza Polgar, Bela Benczur, Alexandra Bodor, 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Saburo Kojima, Masatoshi Komooka, Satoshi Kuroyanagi, Makoto Matsuura, Tetsushi Takemoto, Shuji Yamamoto, Katusmi Saito, Takuro Abe, Issei Ishida, Yuji Iwanami, Shohei Kataoka, Tetsu Moriyama, Akira Murohashi, Akihito Sasaki, Yuichiro Nakamura, Tetsuya Ueno, Akira Shimane, Tomoyo Hamana, Hirotoshi Ichibori, Tomohiro Inoue, Mitsuaki Itoh, Seigo Iwane, Hiroya Kawai, Tatsuya Kokawa, Akiko Masumoto, Koki Matsuo, Taishi Miyata, Shinsuke Nakano, Shogo Oishi, Tetsuari Onishi, Takahiro Sawada, Takayuki Saito, Mitsuhiko Shoda, Nobuyuki Takahashi, Tomofumi Takaya, Yasuyo Taniguchi, Shota Tsukamoto, Yasue Tsukishiro, Yoshiro Tsukiyama, Hiroshi Tsunamoto, Kenzo Uzu, Hiroyuki Yamamoto, Tetsuya Yamamoto, Kiminobu Yokoi, Chiaki Yoshida, Nobuhiro Watanabe, Tetsuo Betsuyaku, Kumiko Adachi, Kouichi Awane, Daisuke Goto, Mamoru Sakakibara, Masashi Watanabe, Hideki Ueno, Yoshitaka Hiroe, Koshi Matsuo, Kenji Ayata, Ko Fukuda, Yoshiki Hata, Katsushi Hashimoto, Hiroaki Matsumi, Akira Nikaido, Shuichi Okamoto, Iveta Sime, Valters Stirna, Ilze Reinholde, Silvija Hansone, Anita Kozlovska, Janina Romanova, Dace Klincare, Natalja Pontaga, Igors Dirmans, Artis Kalnins, Dana Upite, Arcils Gersamija, Arturs Teleznikovs, Nadezda Rozkova, Jelena Safro, Ignasi Anguera Camós, Paolo Domenico Dallaglio, Rafael Salguero Bodes, Fernando Arnbas, Luis Borrego, Alvaro Marco, Javier Ramos Jimenez, Juan José Gómez-Doblas, Alejandro Pérez Cabeza, Ignacio Ferreira Gonzålez, Javier Limeres Freire, Merce Lopez Grau, Xavier Viñolas Prat, Zoraida Moreno Weidmann, Jose Maria Guerra Ramos, Maria Concepcion Alonso Martin, Bieito Campos Garcia, Javier Mauricio Mogro Carranza, Francisco Javier Mendez Zurita, Enrique Rodriguez Font, Carlos Eduardo Gonzales Matos, Víctor García Hernando, Carl-Johan Lindholm, Jörgen Thulin, Håkan Wallén, Kristina Hagwall, Ken Eliasson, Martin Lundvall, Jens Olsson, Björn Kjellman, Markus Lind, Lars Johansson, Niclas Svedberg, Stefan Berglund, Julia Söderberg, Christer Zedigh, Thomas Mooe, Mattias Axelsson, Emil Binsell, Daniel Huber, Christian Müller, Isabelle Danier, Michael Kühne, Bernhard Okamura, Hadrien Schoepfer, Cornelia Simmen, Tobias Reichlin, Laurève Chollet, Anna Lam, Severin Wittmer, Hans Rickli, Christian Gall, Greta Hametner, Stephanie Intorp, Daniel Luescher, Laurent Haegeli, Jan Christopher Berg, Ramin Ebrahimi, Angelo Auricchio, Carmela Crljenica, Tizziano Moccetti, Cristina Monti, Elena Pasotti, Iveta Petrova, Mariagrazia Rossi, François Mach, Mehdi Namdar, Joris de Groot, Virginnio Proost, Joline Neefs, Dominik Linz, Twan van Stipdonk, Dennis den Uijl, Marco Alings, Jeroen Schaap, Dolf Segers, Noemi Wouters, Louis Bartels, Robert Tieleman, Ron Pisters, Tim de Vries, Jaap Selig, Aaf Kuijper, Pieter Bot, Mitran Keijzers, Gerardus Verdel, Raymond Tukkie, Ewout van den Bos, Floris Kauer, Rohit Oemrawsingh, Jeroen Stevenhagen, Jan van Es, Gregory Lip, Dhiraj Gupta, Agnieszka Kotalczyk, Anthony Gunstone, Richard David Brixey, Diana Gorog, Danial Dinarvand, 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Gale Document Number: GALE|A699792860